FI76810C - FRAMEWORK FOR THE FRAMEWORK OF PHARMACEUTICALS THERAPEUTIC THIAZOLO-THIENO-AZEPIN- OCH TIAZOLO-THIENO-PYRIDINDERIVAT. - Google Patents

Abstract

Compounds of the formula <IMAGE> wherein A is <IMAGE> and R is hydrogen, alkyl of 1 to 5 carbon atoms, alkanoyl of 1 to 5 carbon atoms, alkenyl of 3 to 5 carbon atoms, (alkoxy of 1 to 4 carbon atoms)carbonyl, or aralkyl of 7 to 11 carbon atoms optionally halo-substituted, and non-toxic, pharmacologically acceptable acid addition salts thereof. The compounds as well as their salts are useful as bradycardiacs.

Description

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Process for the preparation of pharmaceutically valuable thiazolo-thieno-azepine and thiazolo-thieno-pyridine derivatives. - For the manufacture of pharmaceutical products, thiazolo-thieno-azepine and thiazolo-thieno-pyridine derivatives are used.

The present invention relates to a process for the preparation of pharmacologically active 2-aminotetrahydrothiazolo [4 ', 5': 5.4] thienoazepines and pyridines of the formula I is / CH2Tnf? TNHi wherein jossa is a group of the formula i / CH2- vCH2- ^ CH2-CH2-

R-N R-N or R-N

^ N

wherein R is a hydrogen atom, an alkyl or alkanoyl group having 1 to 5 carbon atoms, an alkenyl group having 3 to 5 carbon atoms, an alkoxycarbonyl group having 2 to 5 carbon atoms or an optionally halogen-substituted benzyl group, and acid addition salts thereof, especially their physiologically acceptable acid addition salts. or with organic acids.

The novel compounds of the formula I have valuable pharmacological properties, namely an effect on the heart and the circulation, in particular, however, an effect on lowering the heart rate.

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Suitable values for the definition of the group R which have already been mentioned are, for example, vatatom, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, tert. pentyl, foryl, acetyl, propionyl, n-butanoyl, n-pentanoyl, 2-methylpropionyl, pivaloyl, allyl, crotyl, penten-2-yl, penten -3-yl, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, benzyl, chlorobenzyl, bromobenzyl or fluorobenzyl.

i

However, the preferred compounds of the invention are 2-aramino-6,7,8,9-tetrahydro-5H-thiazolo / 41.5 ': 5.4 / thieno / 2,3-d / azepine, -amino-5,6,7,8-tetrahydro-thiazolo [4 ', 5': 5,4-thieno [3,2-c] pyridine, 2-amino-5,6,7,8-tetrahydro- thiazolo [41,5 ': 5,4] thieno [2,3-c] pyridine and 2-amino-6,7,8,9-tertahydro-5H-thiazolo [4', 5 ': 5,4 / thieno / 2,3-c) azepine derivatives in which R is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkanoyl group having 1 to 3 carbon atoms, an alkoxycarbonyl group having 2 to 4 carbon atoms, optionally substituted by a chlorine or bromine atom a benzyl group or an allyl group, and their acid addition salts, in particular their physiologically acceptable acid addition salts with inorganic and organic acids.

However, particularly preferred compounds of the present invention are the 2-amino-6,7,8,9-tetrahydro-5H-thiazolo [4 ', 5 *: 5.4 / thieno / 2,3- d) azepine and 2-aramino-5,6,7,8-tetrahydrothiazolo [4 ', 5': 5,4 / thieno [2,3-c] pyridine derivatives in which 3 76810 R is a hydrogen atom, An alkyl group having 1 to 3 carbon atoms, an allyl or benzyl group, and their physiologically acceptable acid addition salts with inorganic or organic acids.

According to the invention, the novel compounds are obtained by the following methods: a) a compound of general formula (II) crr CHa 8 NH2 in which A is as defined above is reacted with dirodane.

The reaction is best carried out in a solvent or solvent mixture such as glacial acetic acid, acetic acid / water, dioxane / acetic acid, methanol, tetrahydrofuran or dilute hydrochloric acid at temperatures between -5 and 50 ° C, but most preferably between 0 and 25 ° C.

In this case, the dirodane required for the reaction is suitably prepared by oxidizing rhodanic acid, for example with chlorine, bromine, a heavy metal salt such as copper sulphate or by anodic oxidation, which rhodanic acid is liberated with sulfuric acid, or dirodane is prepared by decomposing a corresponding heavy metal salt such as copper rhodane.

In addition, a compound of general formula II can be prepared in a reaction mixture by decarboxylation of the corresponding 2-amino-3-carbocaine compound or by hydrolysis followed by decarboxylation of the corresponding alkoxycarbonylamino compound in the presence of an acid, Kuben trifluoroacetic acid, dichloroacetic acid or glacial acetic acid / glacial acetic acid. .

b) for the preparation of a compound of general formula (I) wherein R is methyl or ethyl, reducing a compound of formula I obtained in a) wherein R is a alkoxy carbonyl or acetyl group with lithium aluminum hydride, in the former case a compound of formula I wherein R is methyl and in the latter one wherein R is ethyl.

The reduction is carried out in the presence of a hydride and suitably in a suitable solvent such as diethyl ether, tetrahydrofuran, dioxane or pyridine / tetrahydrofuran at temperatures between 0 and 100 ° C, but preferably at the boiling point of the solvent used. The reduction is performed with lithium aluminum hydride.

The compounds of the general formula I obtained can be further converted into their acid addition salts, in particular into their physiologically acceptable salts with inorganic or organic acids. Suitable acids are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, tartaric acid, maleic acid or fumaric acid.

The compounds of the general formulas II and III used as starting materials, which can be used as crude products, are obtained by methods known from the literature, for example by carrying out the Vilsmeier reaction in the corresponding cyclic ketone, converting the chloroformyl compound thus obtained into oxy? by reacting the resulting nitrile with a thioglycol ester and then cyclizing. The esters thus obtained can be decarboxylated after hydrolysis. The compounds of the general formulas II and III are partially the subject of European patent application Θ2,100,745.7, February 16, 1981, published June 25, 1982 under number 0 058 341, i. they can be prepared by the methods described therein.

DhR patent 92,722 discloses thiazolo and oxazolo [4,4] azepines and their acid addition salts which have valuable pharmacological properties, in particular their antihypertensive and / or antitussive effect.

In order to develop even more pharmacologically effective compounds, the compounds according to the invention described in the present application, in particular having a heart rate-lowering effect, were obtained.

It has already been mentioned above that the new compounds of the general formula I and their physiologically acceptable acid addition salts have valuable pharmacological properties, in particular:

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In addition to the effect on blood pressure, a strong heart rate lowering effect.

For example, the biological properties of the following compounds were studied as follows: A = 7-ethyl-2-amino-6) 7,8,9-tetrahydro-5H-thiazolo [4'5 ': 5,4 / -thieno / 2,3- d) azepine dihydrochloride, B = 2-amino-7-benzyl-6,7,8,9-tetrahydro-5H-thiazolo [4 ', 5': 5,4] -thieno [2,3-d] azepine,; · 11 C = 7-allyl-2-amino-6,7,8,9-tetrahydro-5H-thiazolo [4 ', 5': 5,4] -thieno [2,3-d] azepine -dihydrochloride, O = 2-amino-6,7,8,9-tetrahydro-7-isopropyl-5H-thiazolo [4 ', 3': 5,4] thieno [2,3-d] azepine- d hydrochloride, E = 6-ethyl-2-amino-5,6,7,8-tetrahydrothiazolo [4 ', 5': 5,4] -thieno [2,3-c] pyridine dihydrochloride, F = 2-amino-5,6,7,8-tetrahydro-6-propyl-thiazolo [4 ', 5': 5,4'-thieno [2,3-c] pyridine dihydrochloride, G = 2-amino- 5,6,7,8-tetrahydro-6-methyl-thiazolo [4 ', 5': 5,4 / -thieno [2,3-c] pyridine dihydrochloride and H = 2-amino-5,6,7 , 8-Tetrahydro-5H-thiazolo [4 ', 5': 5,4 / -thieno [2,3-d] azepine dihydrochloride 1. Effect on blood pressure and heart rate

Methods:

Circulatory changes in intravenous test compounds were recorded in uncut, anesthetized rats.

II

7 after injection. 7681 0

Test performance:

Koi ras rats weighing about 200 g are anesthetized with pentobarbital li 11 a (50 mg / kg i.p.). Animals breathe spontaneously through an attached tracheal nail. Blood pressure is measured from the artery of A. carotis using an electromechanical pressure transducer; the heart rate wave triggers a tachograph that continuously registers the heart rate. Both parameters are attached to the polygraph. Test substances are injected through a catheter into the vein of V. jugularis.

At a dose of 3 mg / kg i.v. caused a long-term decrease in blood pressure after a short-term initial rise in blood pressure. The heart rate was clearly and for a long time decreased. The maximum values are shown in the following table:

Compound Dose Blood pressure, mmHg Heart rate mg / kg Ascending- Decreasing, beats / minute i.v. step va step Ä 3 + 52 - 10 I 90 B 3 - 25 - 93

C I

5 + 17-15 - 150 D, 5 + 23-20 - 78 E, 5 + 30-29 - 108 F, 5 + 16-12 - 65 G 3 + 46-30 - 95 H i + 38-34 - 100 2. Effect on presynaptic g-adrenoceptors: inhibitory effect of electrically triggered tachycardia 8 I,

Methodology: 7681 0

The adrenergic end of the nerve has a self-regulatory system for noradrelin release. Stimulation of resynaptic α-adrenoceptors acts to inhibit the release of noradrelin and thus to limit adrenergic neurotransmission.

Stimulation of these "feedback" receptors correspondingly attenuates the effect of adrenergic stimulation in the target organ.

In a model using electrically stimulated spinal rats, presynaptically and α-kinetically effective agents attenuate the electrically induced plexus of the heart.

Test performance:

Male rats weighing 350-400 g are anesthetized with pentobarbital li 11a (50 mg / kg i.p.), dissected by the circulatory nerve, treated with atropine (1 mg / kg s.c.) and tracheacanylated. After removal of the eye, the orbit is punctured, the brain is destroyed, and a metal rod is inserted into the spinal canal. Animals pretreated with ga11amine11a (4 mg / kg i.v.) breathe artificially. The metal rod used is 2.5 mm in diameter and insulated (fire enamelled). Measured from the tip, the rod is bare at a distance of 7 to 8 cm. This bare point comes when the rod is pushed forward to the height of the latter neck and first thorax. The stimulator is used to perform a supernatural stimulation (rectangular pulse 50V, 2 ms; 0.2 Hz; stimulation time 25 s) on a counter electrode inserted into the neck skin of the animal.

Blood pressure is measured from the artery of A. carotis using an electromechanical pressure transducer. A pulse wave triggers a tachograph that continuously provides a heart rate. Both signals are registered to the multi-channel recorder.

A dose (D 2 g) is obtained which inhibits 50% of the electrically induced tachycardia.

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Compound Inhibition of Electrically Triggered Tachycardia __J_ ^ 50_ A 290 ^ g / kg i.v.

3. Effect on postsynaptic α-adrenoceptors; Increase in blood pressure spinaa1iroti11 a:

Method iikka;

In a model using a spinach rat, the increase in blood pressure after stimulation of postsynaptic α-adrenoceptors is measured.

Execution of the test;

Male rats weighing 200-250 g are anesthetized (1.2 g / kg urethane, i.p., 1 mg / kg atropine s.c.). The spinal canal is then opened. At the point of separation of the spinal cord and meta11 a large dila is destroyed by Medulla oblongata and the brain. Animals breathe artificially; a polyethylene catheter is inserted into the jugular vein and blood pressure is recorded from the artery of A. carotis using a Statham element Grass poly-graph.

A dose (D 2 g) is obtained which raises arterial blood pressure by 30 mmHg.

Compound Antihypertensive effect __ ° 30_ A 145 μg / kg i. v.

H 0.36 mg / kg i.v.

- = --- i; ...____ ίο 7681 0 4. Acute toxicity:

The acute toxicity of test compounds was determined in mice after oral or intravenous administration (observation period: 14 days):

Compound LD5Q

A 34 mg / kg i.v. 320 mg / kg p.o.

F> 300 mg / kg p.o.

Based on their pharmacological properties, the new compounds of the general formula I and their physiologically acceptable acid addition salts are suitable for the treatment of cardiovascular diseases, angina pectoris disorders and for lowering the heart rate. For this purpose, these can, optionally in combination with other active ingredients, be processed into customary galenic formulations, such as granules, tablets, capsules, suppositories or solutions. The single dose is 0.02 to 0.3 mg / kg body weight, preferably 0.02 to 0.08 mg / kg body weight, 1 to 3 times a day.

The following examples further illustrate the invention: Preparation of starting materials:

Example A

2-Amino-5,6,7,8-tetrahydro-4H-thieno [2,3-c] azepine-3,7-dicarboxylic acid diethyl ester 3.7 g (0.02 mol) of hexahydro-azepinoone (4) -1-carboxylic acid ethyl ester and 2.26 g (0.02 mol) of cyanoacetic acid ethyl ester and 0.65 g (0.02 mol) of sulfur are added to 20 ml of ethyl alcohol. 5 ml of morpholine are added dropwise to this suspension with stirring, at which point the temperature rises to approx

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11 to 30 ° C. It is then stirred for a further 3 hours at 50 [deg.] C. and allowed to stand overnight at room temperature. The next day, the solid product precipitated in the meantime is filtered off with suction and recrystallized from isopropyl alcohol.

Yield: 3.6 g (58% of theory),

Melting point: 104-106 ° C

Calculated: C 53.86 H 6.41 N 8.98 S 10.25 Found: 53.90 6.40 9.04 10.32

Example B

2-Amino-5,6-7,8-tetrahydro-4H-thieno [2,3-d] azepine-3-carboxylic acid methyl ester hydrochloride

To a solution of 41 g (0.15 moles) of 5-bromo-hexahydro-azepinone- (4) -hydrobromide in 90 ml of methyl alcohol is added dropwise at 10-15 ° C within 25 minutes a solution containing 11, 1 g (0.15 mol) of sodium hydrogen sulphide in 120 ml of methyl alcohol. After stirring for a further 20 minutes, 14.9 g (0.15 mol) of cyanoacetic acid methyl ester are added at 10-15 ° C. 21.9 g (0.3 mol) of diethylamine are then added dropwise with vigorous stirring over a period of 20 minutes, the internal temperature rising from 8 ° C to 26 ° C. It is then stirred for a further 2 hours at 40 [deg.] C.. After cooling, the mixture is evaporated in vacuo, the residue is taken up in dilute sodium hydroxide and shaken with chloroform. The chloroform phases are washed with dilute sodium hydroxide and water, dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed on a silica gel column (chloroform / methanol / aqueous ammonia = 7: 4: 0.25). After combining the corresponding fractions, evaporate in vacuo. The residue is taken up in methanol and the hydrochloride is precipitated by adding isopropyl alcoholic hydrochloric acid, followed by suction separation. The sparingly soluble salt is boiled twice with methanol.

Yield: 5.4 g (13.7% of theory),

Melting point: from 256 ° C (dec.) -Π I1. ___ 7681 0

Calc .: C 45.71 H 5.75 N 10.66 Cl 13.49 S 12.20

Found: 45.67 5.81 10.64 13.50 12.04

Example C

2- (N-tert-butyloxycarbonylamino) -6-propyl-5,6,7,8-tetrahydro-4H-thieno [2,3-d] azepine 8.5 g (0.0335 moles) of 5,6,7,8-tetrahydro- 6-Propyl-4H-thieno [2,3-d] azepine-2-carboxylic acid hydrazide is dissolved in 70 ml of 2N hydrochloric acid and diazotized at -5 to 0 ° C with a solution containing 2.8 g (0.04 moles) of sodium nitrite in 10 ml of water. Stir for a further 50 minutes at 0 ° C and then cover the thick crystalline porridge formed with 150 ml of methylene chloride. 40 ml of concentrated ammonia solution are then added, the methylene chloride phase is separated off and the aqueous layer is extracted several times with methylene chloride.

The combined methylene chloride phases are dried over sodium sulfate and evaporated on a rotary evaporator at a bath temperature of 30 ° C.

Benzene is then added twice more and evaporated in vacuo.

Acid yield: 8.5 g (95.8% of theory), light brown oil.

The compound (0.032 mol) is dissolved in 25 ml of absolute dioxane and a mixture of 30 ml of absolute dioxane and 2.9 g (0.0385 mol) of tert is added dropwise over 30 minutes to a temperature of 90 ° C. butyl alcohol. In this case, strong nitrogen evolution occurs. It is then heated to boiling for a further 1.5 hours and allowed to cool overnight. The next day the mixture is evaporated in vacuo and the residue is chromatographed on a column of silica gel (acetic acid / ethyl alcohol / concentrated aqueous ammonia = 0.2: 7: 0.7). After combining the corresponding fractions, evaporate in vacuo.

Yield: 5.5 g (55% of theory),

Melting point: 141-143 ° C.

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Example D

6-ethyl-2-amino-5,6,7,8-tetrahydro-4H-thieno [2,3-d] azepine dihydrobromide 2.0 g (0.0068 mol) of 6-ethyl-2- (N-tert. -butyloxycarbonylamino) -5,6,7,8-tetrahydro-4H-thieno [2,3-d] azepine with stirring and cooling to 0 ° C in 18 ml of 40% glacial acetic acid and hydrogen bromide. solution while passing dry nitrogen. Stir for 3 hours at 0 [deg.] C., then add dropwise 60 ml of absolute ether, stir for 15 minutes and decant. The absolute ether is added several times and decanted, after which the initially adhesive becomes crystalline and separable by suction. It is washed several more times with absolute ether and dried in a desiccator with phosphorus pentoxide11a. Yield: 1.8 g (75% of theory),

Melting point: from 50 ° C (dec.).

Calc .: C 33.54 H 5.07 N 7.82 Br 44.62 S 8.95

Found: 33.80 5.29 7.36 44.30 8.84

In analogy to Examples A to D, the following compounds were prepared: 2-Amino-6-benzyl-5,6,7,8-tetrahydro-4H-thieno [2,3-d] azepine-3-carboxylic acid ethyl ester hydrochloride Yield: 23% of theory,

Melting point: 228-229 ° C (dec.)

Calc .: C 58.93 H 6.32 N 7.63 Cl 9.66 S 8.74

Found: 58.64 6.32 7.36 9.34 8.52 6-ethyl-2-amino-5,6,7,8-tetrahydro-4H-thieno [2,3-d] azepine-3 -carboxylic acid ethyl ester oxalate Yield: 32% of theory Melting point: 173-174 ° C (iia j) 14

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Calc .: C 50.27 H 6.19 N 7.82 S 8.94

Found: 50.25 6.36 7.64 9.23 6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thieno [2,3-d] azine-3-carboxylic acid ethyl ester

Yield: 26.1% of theory, red oil

Calc .: Molar peak m / e = 280

Found: Molecular peak m / e = 280 2-amino-5,6,7,8-tetrahydro-4H-thieno [2,3-d] azepine-3,6-dicarboxylic acid diethyl ester and 2-amino-5,6, 7,8-Tetrahydro-4H-thieno [2,3-c] azepine-3,7-dicarboxylic acid diethyl ester

Yield: 16.1% of theory

Melting point: 122-125 ° C

Calculated: C 53.83 H 6.45 N 8.97 S 10.26 Found: 54.00 6.35 9.16 10.06 2- (N-tert-butyloxycarbonylamino) -5.6.7, 8-Tetrahydro-6-isopropyl-4H-thieno [2,3-d] azepine

Yield: 38.5 S of theory

Calc .: C 61.90 H 8.44 N 9.02 S 10.33

Found: 61.68 8.56 9.18 10.19 2-amino-5,6,7,8-tetrahydro-6-isopropyl-4H-thieno [2,3-d] azepine dihydrobromide Yield: 83, 5% of theoretical

Calc .: C 35.50 H 5.42 N 7.53 S 8.61 Br 42.94

Found: 35.19 5.63 7.64 8.32 42.51

6-Allyl-2- (N-tert-butyloxycarbonylamino) -5,6,7,8-tetrahydro-4H-thieno [2,3-d] azepine Yield: 29.6% of theory Melting point: 135-137 ° C

Calc .: C 62.31 H 7.84 N 9.08 S 10.39

Found: 62.40 7.93 9.06 10.50

II

15,768,0 6-Allyl-2-amino-5,6,7,8-tetrahydro-4H-thieno [2,3-d] azepine dihydrbromide

Yield: 83.3% of theory Melting point: from 50 ° C (dec.)

Calc .: C 35.69 H 4.90 N 7.57 Br 43.18 S 8.66

Found: 35.70 5.33 6.95 42.70 8.36 2-amino-6- (4-chlorobenzyl) -5,6,7,8-tetrahydro-4H-thieno [2,3- d / azepine dihydrobromide Yield: 75% of theory Melting point: from 225 ° C (dec.)

Calculation: Molar peak m / e s 292/294 (1 Cl)

Found: Molar peak m / e = 292/294 (1 Cl) 6-Benzyl-2- (N-tert-butyloxycarbonylamino) -5,6,7,8-tetrahydro-4H-thieno [2,3-d] azepine

Yield: 45% of theory, yellow oil

Calc .: Molar peak m / e s 358

Obtained: Molecular peak m / e s 358 2-Amino-6-benzyl-5,6,7,8-tetrahydro-4H-thieno [2,3-d] azepine dihydrobromide Yield: 84% of theory,

Melting point: 232-234 ° C

Calc .: C 42.87 H 4.80 N 6.67 Br 38.03 S 7.63

Found: 42.90 4.87 6.37 37.90 7.80 6-ethyl-2- (N-tert-butyloxycarbonylamino) -5,6,7,8-tetrahydro-4H-thieno / 2,3- d / azepine

Yield: 30.5% of theory

Melting point: 149-151 ° C

Calc .: C 60.78 H 8.16 N 9.45 S 10.82

Found: 61.00 8.22 9.40 11.04 5-ethyl-2- (N-tert-butyloxycarbonyl) -5,6,7,8-tetrahydro-4H-thieno / 3,2-c / azepine Yield: 67.5% of theory, 16,7681 0 ·

Melting point: 154-156 ° C

5-Ethyl-2-amino-5,6,7,8-tetrahydro-4H-thieno [3,2-c] epepine dihydrochloride

Yield: 100% of theory (hygroscopic)

Melting point; Sintering from 100 ° C, from 210 ° C (dec.).

Manufacture of finished products;

Example 1 7-Ethyl-2-amino-6,7,8,9-tetrahydro-5H-thiazolo [4,5] 5,4-thieno [2,3-d] azepine dihydrochloride 16.9 g ( 0.063 mol) of 6-ethyl-2-amino-5,6,7,8-tetrahydro-4H-thieno [2,3-d] azepine dihydrochloride in 200 ml of glacial acetic acid to which 10 ml of water have been added is stirred. until it dissolves completely. A solution of 36.6 g (0.37 mol) of potassium rhodanide in 40 ml of water is then added slowly and a solution of 10.0 g of bromine (0.063 mol) in 30 ml of glacial acetic acid is slowly added dropwise. After quenching the reaction, stir for an additional hour and allow to stand overnight. After filtration of the insoluble constituents, the mixture is evaporated in vacuo, the black residue is triturated several times with warm water and sucked through the elite each time. The combined aqueous filtrates are basified with concentrated ammonia, cooled in ice water, the precipitated solid is filtered off with suction and washed twice with cold water. After drying, the substance is stirred for three hours in chloroform at room temperature, filtered off with suction, washed with cold chloroform and dried.

The light brown crystals are dissolved in hot methanol by adding a little chloroform and acidified with ethanolic hydrochloric acid. After cooling in ice water, the dihydrochloride is filtered off with suction and dried.

II

17 76810

Yield: 6 g (30% of theory),

Melting point: 256 ° C (dec.)

Calc .: C 40.49 H 5.25 Cl 21.73 N 12.88 S 19.65

Found: 40.60 5.12 21.55 13.01 19.50

Example 2 2-Amino-7-benzyl-6,7,8,9-tetrahydro-5H-thiazolo [4,5,5] -thieno [2,3-d] azepine

Prepared according to Example 1 from 2-amino-6-benzyl-5,6,7,8-tetrahydro-4H-thieno [2,3-d] azepine dihydrochloride, kaumrodanide and bromine.

Yield: 56% of theory,

Melting point: 191-192 ° C

Calc .: C 60.92 H 5.43 N 13.32 S 20.33

Found: 61.24 5.53 12.97 20.45

Example 3 2-Amino-7- (4-chlorobenzyl) -6,7,8,9-tetrahydro-5H-thiazolo [41,5 ': 5.4 / thieno [2,3-d] azepine dihydrochloride

Prepared according to Example 1 from 2-amino-6- (4-chlorobenzyl) -5,6,7,8-tetrahydro-4H-thieno [2,3-d] azepine dihydrochloride, including liumrodanide and bromine.

Yield: 12% of theory Melting point: 220 ° C (dec.)

Calc .: C 45.45 H 4.29 Cl 25.15 N 9.94 S 15.17

Found: 45.60 4.15 25.10 10.02 15.35

Example 4 2-Amino-7-propyl-6,7,8,9-tetrahydro-5H-thiazolo [4,51: 5,4] thieno [2,3-d] azepine dihydrochloride

Prepared according to Example 1 for 2-amino-6-propyl

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18 5,6,7,8-Tetrahydro-4H-thieno [2,3-d] azepine dihydrochloride, including potassium rhodanide and bromine.

Yield: 22% of theory Melting point: 230-233 ° C (dec.)

Calc .: g 42.35 H 5.63 Cl 20.83 N 12.35 S 18.84

Found: 42.25 5.79 20.45 12.50 18.95

Example 5 2-Amino-7-isopropyl-6,7,8,8,9-tetrahydro-5H-thiazolo [4,5 ': 5,4 / thieno [2,3-d] azepine dihydrochloride

Prepared according to Example 1 from 2-amino-5,6,7,8-tetrahydro-6-isopropyl-4H-thieno [2,3-d] azepine dihydrochloride, potassium rhodanide and bromine.

Yield: 28% of theory Melting point: 243-245 ° C (dec.)

Calc .: C 42.35 H 5.63 Cl 20.83 N 12.35 S 18.84

Found: 42.35 6.00 21.00 12.27 18.85

Example 6 7-Ethyl-2-amino-5,6,7,7-tetrahydrothiazolo [4,5-b] 5,4-thieno [3,2-c] pyridine hydrochloride

Prepared according to Example 1 from 2-amino-5-ethyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridine, potassium rhodanide and bromine.

Yield: 24% of theory Melting point: 250 ° C

Calc .: C 38.46 H 4.84 Cl 22.71 N 13.46 S 20.53

Found: 38.68 4.90 22.52 13.41 20.30

Example 7 2-Amino-7-propyl-5,6t-7,8-tetrahydrothiazolo [4,111: 5,4] -thieno [3,2-c] pyridine dihydrochloride

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19

Prepared according to the first example 1 from 2-amino-5-propyl-4.5,6,7-tetrahydrothieno [3,2-c] pyridine, potassium rhodanide and bromine.

Yield: 29% of theory Melting point: 252-255 ° C (dec.) M.p .: C 40.49 H 5.25 Cl 21.73 N 12.88 S 19.65

Found: 40.45 5.30 21.70 13.02 19.65

Example 8 2-Amino-7-isopropyl-5,6,7,8-tetrahydro-thiazolo [4,5-b] 5,4/-thieno / 3,2-c / pyridine dihydrochloride

Prepared according to Example 1 from 2-amino-5-isopropyl-4.5,6,7-tetrahydrothieno [3,2-c] pyridine, potassium rhodanide and bromine.

Yield: 23% of theory,

Melting point: 271-273 ° C (dec.)

Calc .: C 40.49 H 5.25 Cl 21.73 N 12.88 S 19.65

Found: 40.71 5.21 21.72 12.91 19.43

Example 9 7-Allyl-2-amino-5,6,7,8-tetrahydro-thiazolo [4,1,5]: 5,4-thieno [3,2-c] pyridine dihydrochloride

Prepared according to Example 1 from 5-allyl-2-amino-4.5,6,7-tetrahydro-thieno [3,2-c] pyridine, potassiumrdanid and bromine.

Yield: 22% of theory Melting point: 246-247 ° C (dec.)

Calc .: C 40.74 H 4.66 Cl 21.87 N 12.96 S 19.77

Found: 40.52 4.90 21.80 13.06 19.77

Example 10 7681 0 20 2-Amino-6,7,8,9-tetrahydro-5H-thiazolo Solo [4,5] 5,4-thio-72. 3-dimethyl-7-carboxylic acid ethyl ester hydrochloride 7.6 g (0.025 mol) of 2-amino-6-carbethoxy-5,6,7,8-tetrahydro-4H-thieno [2,3-d] azepine-3-carboxylic acid sodium salt (prepared by saponification of 7.8 g (0.025 mol) of 2-amino-5,6,7,8-tetrahydro-4H-thieno / 2, 3-d / azepine-3,6-dicarboxylic acid diethyl ester with sodium hydroxide) is dissolved in 125 ml of glacial acetic acid and 7.3 g (0.075 mol) of potassium rhodanide and 12.5 ml of water are added. A solution of 4 g (0.025 mol) of bromine in 17 ml of glacial acetic acid is added dropwise to the reaction mixture with stirring and stirred for a further 3 hours at room temperature. It is then poured into 500 ml of water, made alkaline with concentrated aqueous ammonia and extracted five times with chloroform. The combined chloroform extracts are washed 3-4 times with water, dried over sodium sulfate and potassium carbonate and evaporated in vacuo.

The solid residue is purified by chromatography twice on a silica gel column (150 ml; chloroform / methanol = 100: 3 and chloroform / ethyl acetate = 17: 3). The corresponding fractions are evaporated in vacuo, then the residue is dissolved in a 10: 1 mixture of chloroform and methanol and acidified with isopropanolic hydrochloric acid. The reaction mixture is then evaporated once more in vacuo, the residue is boiled in ethyl acetate and filtered off with suction in ice water after cooling. Yield: 1.7 g (20.4 S of theory)

Melting point: 212 ° C (dec.)

Calc .: C 43.17 H 4.83 Cl 10.62 N 12.50 S 19.21

Found: 43.31 5.01 10.75 12.79 19.45

Example 11 1 .......... '2-amino-6,7,8,9-tetrahydro-5H-thiazolo [4,5': 5,4 / thieno [2,3-d] azepine dihydrochloride

II

76810-

Prepared according to Example 10 from 2-amino-5,6,7,8-tetrahydro-4H-thieno [2,3-d] azepine-3-carboxylic acid sodium salt, potassium rhodanide and bromine.

Yield: 22.3% of theoretical,

Melting point: 310 ° C

task: C 36.24 H 4.39 Cl 23.77 N 14.09 S 21.50

Found: 36.01 4.58 23.60 13.75 21.30

Example 12 7-Allyl-2-amino-6,7,8,9-tetrahydro-5H-thiazolo [4 '. 5 *: 5.4 / -thieno [2,3-d] azepine dihydrochloride

Prepared according to Example 10 from 6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thieno [2,3-d] azepine-3-carboxylic acid sodium salt, potassium rhodanide and bromine.

Yield: 15% of theory,

Melting point: 232-233 ° C (dec.)

Calc .: C 42.60 H 5.06 Cl 20.96 N 12.42 S 18.95

Found: 42.89 4.96 20.80 12.78 18.80

Example 13 2-Amino-5,6,7,8-tetrahydro-6-isopropyl-thiazolo [4,5] 5,4-thieno [2,3-c] pyridine dihydrochloride

Prepared according to Example 10 from the sodium salt of 2-amino-6-isopropyl-4,5-1,7,7-tetrahydrothieno [2,3-c] pyridine-3-carboxylic acid, potassium rhodanide and bromine.

Yield: 24.5% of theory Melting point: 250 ° C (dec.)

Calc .: C 40.49 H 5.25 Cl 21.73 N 12.88 S 19.65

Found: 40.54 5.26 21.80 13.08 19.45 22 7681 0

Example 14 6-Allyl-2-amino-5,6,7,8-tetrahydro-thiazolo / 4-thieno [2,3-c] pyridine dihydrochloride

Prepared according to Example 10 from 6-allyl-2-amino-4.5,6,7-tetrahydro-thieno [2,3-c] pyridine-3-carboxylic acid sodium salt, potassium rhodanide and bromine.

Yield: 7% of theory Melting point: 165 ° C (dec.)

Calc .: C 40.74 H 4.66 Cl 21.87 N 12.96 S 19.77

Found: 40.60 4.79 21.88 12.96 19.70

Example 15 6-Ethyl-2-amino-5,6,7,8-tetrahydro-thiazolo [4',5 ': 5,4-thieno [2,3-c] pyridine dihydrochloride

Prepared according to Example 10 from 6-ethyl-2-amino-4,5,6,7-tetrahydrothieno [2,3-c] pyridine-3-carboxylic acid sodium salt, potassium rhodanide and bromine.

Yield: 12% of theory Melting point: 237 ° C (dec.)

Calc .: C 38.46 H 4.84 Cl 22.71 N 13.46 S 20.54

Found: 38.25 4.84 22.40 13.40 20.20

Example 16 2-Amino-6-propyl-5,6,7,8-tetrahydro-thiazolo [4'-5t: 5,4-thieno [2,3-c] pyridine dihydrochloride

Prepared according to Example 10 from 2-amino-6-propyl-4.5,6,7-tetrahydro-thieno [2,3-c] pyridine-3-carboxylic acid sodium salt, potassium rhodanide and bromine.

Yield: 12% of theory Melting point: 224 ° C (dec.) 7681.0 23

Calc .: C 40.49 H 5.25 Cl 21.73 N 12.88 S 19.65

Found: 40.64 5.41 21.54 13.28 19.90

Example 17 2-Amino-6-methyl-5,6,7,8-tetrahydro-thiazolo [4], 5,4-thieno [2,3-c] pyridine hydrochloride

Prepared according to Example 10 from 2-amino-6-methyl-4.5,6,7-tetrahydro-thieno [2,3-c] pyridine-3-carboxylic acid sodium salt, potassium rhodanide and bromine.

Yield: 4% of theory,

Melting point: 260-262 ° C (dec.)

Calc .: C 36.24 H 4.39 Cl 23.77 N 14.09 S 21.50

Found: 36.15 4.37 23.65 13.96 21.40

Example 18 6-Acetyl-2-amino-5,6-7,8-tetrahydro-thiazolo [4'-5 *: 5,4'-thieno [2,3-c] pyridine hydrochloride

Prepared according to Example 10 from 6-acetyl-2-amino-4.5,6,7-tetrahydro-thieno [2,3-c] pyridine-3-carboxylic acid sodium salt, potassium rhodanide and bromine.

Yield: 5% of theory,

Melting point: 215 ° C (dec.)

Calc .: C 41.44 H 4.17 Cl 12.23 N 14.50 S 22.13

Found: 41.77 3.98 12.42 14.50 22.00

Example 19 2-Amino-7-methyl-5,6,7,8-tetrahydrothiazolo [4 ', 5': 5,4-thieno [3,2-c] pyridine dihydrochloride

Prepared according to Example 10 from 2-amino-6-methyl-4.5,6,7-tetrahydro-thieno [3,2-c] pyridine-3-carboxylic acid sodium salt, potassium rhodanide and bromine.

24 76810

Yield: 5.4% of theory Melting point: 259-260 ° C (dec.)

Calc .: Mole peak m / e s 225 Obtained: Mole peak m / e = 225

Example 20 2-Amino-6,7,8,9-tetrahydro-7-methyl-5H-thiazolo [4 ', 5': 5,4'-thieno [2,3-d] azepine dihydrochloride 3 g (0, 01 mol) 2-Amino-6,7,8,9-tetrahydro-5H-thiazolo [4 ', 5': 5,4] thieno [2,3-d] azepine-7-carboxylic acid ethyl ester is dissolved in 30 ml. to absolute tetrahydrofuran and slowly added dropwise with stirring at room temperature to a suspension of 3 g (0.08 mol) of lithium aluminum hydride in 50 ml of absolute tetrahydrofuran. The temperature of the reaction mixture is then kept below 30 ° C by occasional cooling in ice water. Stir for an additional 6 hours at room temperature and allow to stand overnight. The next day, 18 ml of acetic acid ethyl acetate are added dropwise slowly and under ice-cooling, keeping the temperature below 25 ° C. Then 10 ml of water and 3 ml of 10% sodium hydroxide are carefully added. The hydroxy precipitate is filtered off with suction and washed several times with a hot mixture of chloroform and methanol or chloroform. After evaporation of the filtrate, 3 g of a viscous dark oil remain, which is purified by column chromatography on silica gel (chloroform / methanol / concentrated aqueous ammonia = 8.5: 1.5: 0.15). After evaporation of the corresponding fractions, the residue is dissolved in isopropanol and acidified with isopropanol-containing hydrochloric acid. The precipitated dihydrochloride is filtered off with suction and washed with cold isopropanol.

Yield: 0.55 g (18% of theory)

Melting point: 271-273 ° C (dec.) M.p .: C 38.46 H 4.84 Cl 22.71 N 13.46 S 20.53

Found: 38.80 4.50 22.90 13.37 20.55

Example 21

7681 O

2-Amino-6,7,8t9-tetrahydro-6-methyl-5H-thiazolo [4 ', 5': 5,4-thieno [2,3-c] azepine dihydrochloride

Prepared according to Example 20 by reduction of 2-amino-6-carbethoxy-6,7,9-tetrahydro-5H-thiazolo [4 ', 5': 5,4] thieno [2,3-c] azepine with lithium aluminum hydride.

Yield: 26% of theory Melting point: 217-220 ° C (dec.)

Calc .: C 38.46 H 4.84 Cl 22.71 N 13.46 S 20.53

Found: 38.25 4.99 22.50 13.54 20.25

Example 22 6-Ethyl-2-amino-5,6,7t 8-tetrahydro-thiazolo / 4-thieno [2,3-c] pyridine dihydrochloride

Prepared according to Example 20 by reduction of 6-acetyl-2-amino-5,6,7,8-tetrahydrothiazolo [4 ', 5': 5,4] thieno [2,3-c] pyridine with lithium aluminum hydride.

Yield: 29 Theoretical Melting point: 237 ° C (dec.)

Calculation: Molar peak m / e = 239 Found: Molar peak m / e = 239

Example 23 8-Ethyl-2-amino-6,7,8t9-tetrahydro-5H-thiazolo / 4 1.5 ': 5.4 / -thieno [3,2-c] azepine dihydrochloride

Prepared according to Example 1 from 5-ethyl-2-amino-5,6,7,8-tetrahydro-4H-thieno [3,2-c] azepine dihydrobromide, including liumrodanide and bromine.

Yield: 21% of theory Melting point: 241-242 ° C (dec.)

7681 O

26

Calc .: C 40.49 H 5.25 Cl 21.73 N 12.88 S 19.65

Found: 40.97 5.34 22.05 13.07 20.15

Example 24 2-Amino-7- (2-chlorobenzyl) -6,7,8,9-tetrahydro-5H-thiazolo [4 ', 5 1: 5,4 / thieno [2,3-d] azepine dihydrochloride

Prepared according to Example 1 from 2-amino-6- (2-chlorobenzyl) -5,6,7,8-tetrahydro-4H-thieno [2,3-d] azepine dihydrochloride, potassium rhodamide and bromine or using as oxidant copper sulphate.

Yield: 18% of theory Melting point: 203-206 ° C (dec.)

Calc .: C 45.45 H 4.29 N 9.94 S 15.17

Found: 45.21 4.17 9.83 15.15

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Claims (1)

7681 O '27 A process for the preparation of pharmacologically active 2-amino-tetrahydrothiazolo [4', 5 ': 5.4] thienoazepines and pyridines of the formula I / CH2 V._s \ N ^ NH2 \ I \ Il < 11 N ch2 S ^ - N where A is a group of the formula / CH2- yCH2- .CH2-CH2- RN RN or RN nch2-, \ N wherein R is a hydrogen atom, an alkyl or alkanoyl group having 1 to 5 carbon atoms, 3- An alkenyl group having 5 carbon atoms, an alkoxycarbonyl group having 2 to 5 carbon atoms in total or a benzyl group optionally substituted by a halogen atom, and their acid addition salts, especially their physiologically acceptable acid addition salts with inorganic or organic acids, characterized in that a) a compound of general formula (II). - n 1 I (I1 'x CH2 S NH2 in which · A is as defined above is reacted with dirodane or b) for the preparation of a compound of general formula (I) in which R is methyl or ethyl, reducing such in point a a compound of formula I wherein R is an alkoxycarbonyl or acetyl group with lithium aluminum hydride, in the former case a compound of formula I wherein R is methyl and in the latter a compound wherein R is ethyl and the compound of general formula I thus obtained is optionally converted into its acid addition salt, in particular its physiologically acceptable acid addition salt with an inorganic or organic acid. i i II 29 7681 O Förfarande för framst.ällning av pharmacologiskt. effect of 2-amino-tetrahydrotiazolo [4 ', 5': 5,4 / thienoazepine and pyridine in the form of I / Cll2 -ff \ NH2 »1 i T ci» ^ CH2 S ^ N is a group of formeln, CH2- CH2- ^ Cl ^ -CHj- RV RN or RN ch2-, ^ N varvid R är en väteatom, en. kolatoms alk-oxikarbonyIgrupp eller eventuel.lt en med halogenatom substitu-tuerad benzylgrupp, och deras syraadditionssalter, speciel.lt deras physiologiskt therm.liga syraadditionssalter, med org-niska eller organiciska syror, kännetecknat av fig a) enän förening med (II), <"TX" CH2 8 NH2 is a mixture of the same mixture, which is reacted with the reagent or b) for the purpose of the reaction with all the formulas (I)